This invention relates to the use of a group of aryl ureas in treating cytokine mediated diseases and proteolytic enzyme mediated diseases, and pharmaceutical compositions for use in such therapy.
Two classes of effector molecules which are critical for the progression of rheumatoid arthritis are pro-inflammatory cytokines and tissue degrading proteases. Recently, a family of kinases was described which is instrumental in controlling the transcription and translation of the structural genes coding for these effector molecules.
The MAP kinase family is made up of a series of structurally related proline-directed serine/threonine kinases which are activated either by growth factors (such as EGF) and phorbol esters (ERK), or by IL-1, TNFxcex1 or stress (p38, JNK). The MAP kinases are responsible for the activation of a wide variety of transcription factors and proteins involved in transcriptional control of cytokine production. A pair of novel protein kinases involved in the regulation of cytokine synthesis was recently described by a group from SmithKline Beecham (Lee et al. Nature 1994, 372, 739). These enzymes were isolated based on their affinity to bond to a class of compounds, named CSAIDs cytokine suppressive anti-inflammatory drugs) by SKB. The CSAIDs, pyridinyl imidazoles, have been shown to have cytokine inhibitory activity both in vitro and in vivo. The isolated enzymes, CSBP-1 and -2 (CSAID binding protein 1 and 2) have been cloned and expressed. A murine homologue for CSBP-2, p38, has also been reported (Han et al. Science 1994, 265, 808).
Early studies suggested that CSAIDs function by interfering with m-RNA translational events during cytokine biosynthesis. Inhibition of p38 has been shown to inhibit both cytokine production (eg., TNFxcex1, IL-1, IL-6, IL-8; Lee et al. N.Y. Acad. Sci. 1993, 696, 149) and proteolytic enzyme production (eg., MMP-1, MMP-3; Ridley et al. J. Immunol. 1997, 158, 3165) in vitro and/or in vivo.
Clinical studies have linked TNFxcex1 production and/or signaling to a number of diseases including rheumatoid arthritis (Maini. J. Royal Coll. Physicians London 1996, 30, 344). In addition, excessive levels of TNFxcex1 have been implicated in a wide variety of inflammatory and/or immunomodulatory diseases, including acute rheumatic fever (Yegin et al. Lancet 1997, 349, 170), bone resorption (Pacifici et al. J. Clin. Endocrinol. Metabol. 1997, 82, 29), postmenopausal osteoporosis (Pacifici et al. J. Bone Mineral Res. 1996, 11, 1043), sepsis (Blackwell et al. Br. J. Anaesth. 1996, 77, 110), gram negative sepsis (Debets et al. Prog. Clin. Biol. Res. 1989, 308, 463), septic shock (Tracey et al. Nature 1987, 330, 662; Girardin et al. New England J. Med. 1988, 319, 397), endotoxic shock (Beutler et al. Science 1985, 229, 869; Ashkenasi et al. Proc. Nat""l. Acad. Sci. USA 1991, 88, 10535), toxic shock syndrome (Saha et al. J. Immunol. 1996, 157, 3869; Lina et al. FEMS Immunol. Med. Microbiol. 1996, 13, 81), systemic inflammatory response syndrome (Anon. Crit. Care Med. 1992, 20, 864), inflammatory bowel diseases (Stokkers et al. J. Inflamm. 1995-6, 47, 97) including Crohn""s disease (van Deventer et al. Aliment. Pharmacol. Therapeu. 1996, 10 (Suppl. 2), 107; van Dullemen et al. Gastroenterology 1995, 109, 129) and ulcerative colitis (Masuda et al. J. Clin. Lab. Immmunol. 1995, 46, 111), Jarisch-Herxheimer reactions (Fekade et al. New England J. Med. 1996, 335, 311), asthma (Amrani et al. Rev. Malad. Respir. 1996, 13, 539), adult respiratory distress syndrome (Roten et al. Am. Rev. Respir. Dis. 1991, 143, 590; Suter et al. Am. Rev. Respir. Dis. 1992, 145, 1016), acute pulmonary fibrotic diseases (Pan et al. Pathol. Int. 1996, 46, 91), pulmonary sarcoidosis (Ishioka et al. Sarcoidosis Vasculitis Diffuse Lung Dis. 1996, 13, 139), allergic respiratory diseases (Casale et al. Am. J. Respir. Cell Mol. Biol. 1996, 15, 35), silicosis (Gossart et al. J. Immunol. 1996, 156, 1540; Vanhee et al. Eur. Respir. J. 1995, 8, 834), coal worker""s pneumoconiosis (Borm et al. Am. Rev. Respir. Dis. 1988, 138, 1589), alveolar injury (Horinouchi et al. Am. J. Respir. Cell Mol. Biol. 1996, 14, 1044), hepatic failure (Gantner et al. J. Pharmacol. Exp. Therap. 1997, 280, 53), liver disease during acute inflammation (Kim et al. J. Biol. Chem. 1997, 272, 1402), severe alcoholic hepatitis (Bird et al. Ann. Intern. Med. 1990, 112, 917), malaria (Grau et al. Immunol. Rev. 1989, 112, 49; Taverne et al. Parasitol. Today 1996, 12, 290) including Plasmodium falciparum malaria (Perlmann et al. Infect. Immunit. 1997, 65, 116) and cerebral malaria (Rudin et al. Am. J. Pathol. 1997, 150, 257), non-insulin-dependent diabetes mellitus (NIDDM; Stephens et al. J. Biol. Chem. 1997, 272, 971; Ofei et al. Diabetes 1996, 45, 881), congestive heart failure (Doyama et al. Int. J. Cardiol. 1996, 54, 217; McMurray et al. Br. Heart J. 1991, 66, 356), damage following heart disease (Malkiel et al. Mol. Med. Today 1996, 2, 336), atherosclerosis (Parums et al. J. Pathol. 1996, 179, A46), Alzheimer""s disease (Fagarasan et al. Brain Res. 1996, 723, 231; Aisen et al. Gerontology 1997, 43, 143), acute encephalitis (Ichiyama et al. J. Neurol. 1996, 243, 457), brain injury (Cannon et al. Crit. Care Med. 1992, 20, 1414; Hansbrough et al. Surg. Clin. N. Am. 1987, 67, 69; Marano et al. Surg. Gynecol. Obstetr. 1990, 170, 32), multiple sclerosis (M. S.; Coyle. Adv. Neuroimmunol. 1996, 6, 143; Matusevicius et al. J. Neuroimmunol. 1996, 66, 115) including demyelation and oligiodendrocyte loss in multiple sclerosis (Brosnan et al. Brain Pathol. 1996, 6, 243), advanced cancer (MucWierzgon et al. J. Biol. Regulators Homeostatic Agents 1996, 10, 25), lymphoid malignancies (Levy et al. Crit. Rev. Immunol. 1996, 16, 31), pancreatitis (Exley et al. Gut 1992, 33, 1126) including systemic complications in acute pancreatitis (McKay et al. Br. J. Surg. 1996, 83, 919), impaired wound healing in infection inflammation and cancer (Buck et al. Am. J. Pathol. 1996, 149, 195), myelodysplastic syndromes (Raza et al. Int. J. Hematol. 1996, 63, 265), systemic lupus erythematosus (Maury et al. Arthritis Rheum. 1989, 32, 146), biliary cirrhosis (Miller et al. Am. J. Gasteroenterolog. 1992, 87, 465), bowel necrosis (Sun et al. J. Clin. Invest. 1988, 81, 1328), psoriasis (Christophers. Austr. J. Dermatol. 1996, 37, S4), radiation injury (Redlich et al. J. Immunol. 1996, 157, 1705), and toxicity following administration of monoclonal antibodies such as OKT3 (Brod et al. Neurology 1996, 46, 1633). THFxcex1 levels have also been related to host-versus-graft reactions (Piguet et al. Immunol. Ser. 1992, 56, 409) including ischemia reperfusion injury (Colletti et al. J. Clin. Invest. 1989, 85, 1333) and allograft rejections including those of the kidney (Maury et al. J. Exp. Med. 1987, 166, 1132), liver (Imagawa et al. Transplantation 1990, 50, 219), heart (Bolling et al. Transplantation 1992, 53, 283), and skin (Stevens et al. Transplant. Proc. 1990, 22, 1924), lung allograft rejection (Grossman et al. Immunol. Allergy Clin. N. Am. 1989, 9, 153) including chronic lung allograft rejection (obliterative bronchitis; LoCicero et al. J. Thorac. Cardiovasc. Surg. 1990, 99, 1059), as well as complications due to total hip replacement (Cirino et al. Life Sci. 1996, 59, 86). THFxcex1 has also been linked to infectious diseases (review: Beutler et al. Crit. Care Med. 1993, 21, 5423; Degre. Biotherapy 1996, 8, 219) including tuberculosis (Rook et al. Med. Malad. Infect. 1996, 26, 904), Helicobacter pylori infection during peptic ulcer disease (Beales et al. Gastroenterology 1997, 112, 136), Chaga""s disease resulting from Trypanosoma cruzi infection (Chandrasekar et al. Biochem. Biophys. Res. Commun. 1996, 223, 365), effects of Shiga-like toxin resulting from E. coli infection (Harel et al. J. Clin. Invest. 1992, 56, 40), the effects of enterotoxin A resulting from Staphylococcus infection (Fischer et al. J. Immunol. 1990, 144, 4663), meningococcal infection (Waage et al. Lancet 1987, 355; Ossege et al. J. Neurolog. Sci. 1996, 144, 1), and infections from Borrelia burgdorferi (Brandt et al. Infect. Immunol. 1990, 58, 983), Treponema pallidum (Chamberlin et al. Infect. Immunol. 1989, 57, 2872), cytomegalovirus (CMV; Geist et al. Am. J. Respir. Cell Mol. Biol. 1997, 16, 31), influenza virus (Beutler et al. Clin. Res. 1986, 34, 491a), Sendai virus (Goldfield et al. Proc. Nat""l. Acad. Sci. USA 1989, 87, 1490), Theiler""s encephalomyelitis virus (Sierra et al. Immunology 1993, 78, 399), and the human immunodeficiency virus (HIV; Poli. Proc. Nat""l. Acad. Sci. USA 1990, 87, 782; Vyakaram et al. AIDS 1990, 4, 21; Badley et al. J. Exp. Med. 1997, 185, 55).
Because inhibition of p38 leads to inhibition of TNFxcex1 production, p38 inhibitors will be useful in treatment of the above listed diseases.
A number of diseases are mediated by excess or undesired matrix-destroying metalloprotease (MMP) activity or by an imbalance in the ratio of the MMPs to the tissue inhibitors of metalloproteinases (TIMPs). These include osteoarthritis (Woessner et al. J. Biol. Chem. 1984, 259, 3633), rheumatoid arthritis (Mullins et al. Biochim. Biophys. Acta 1983, 695, 117; Woolley et al. Arthritis Rheum. 1977, 20, 1231; Gravallese et al. Arthritis Rheum. 1991, 34, 1076), septic arthritis (Williams et al. Arthritis Rheum. 1990, 33, 533), tumor metastasis (Reich et al. Cancer Res. 1988, 48, 3307; Matrisian et al. Proc. Nat""l. Acad. Sci., USA 1986, 83, 9413), periodontal diseases (Overall et al. J. Periodontal Res. 1987, 22, 81), corneal ulceration (Burns et al. Invest. Opthalmol. Vis. Sci. 1989, 30, 1569), proteinuria (Baricos et al. Biochem. J. 1988, 254, 609), coronary thrombosis from atherosclerotic plaque rupture (Henney et al. Proc. Nat""l. Acad. Sci., USA 1991, 88, 8154), aneurysmal aortic disease (Vine et al. Clin. Sci. 1991, 81, 233), dystrophobic epidermolysis bullosa (Kronberger et al. J. Invest. Dermatol. 1982, 79, 208), degenerative cartilage loss following traumatic joint injury, osteopenias mediated by MMP activity, tempero mandibular joint disease, and demyelating diseases of the nervous system (Chantry et al. J. Neurochem. 1988, 50, 688).
Because inhibition of p38 leads to inhibition of MMP production, p38 inhibitors will be useful in treatment of the above listed diseases.
Inhibitors of p38 are active in animal models of TNFxcex1 production, including a murine lipopolysaccharide (LPS) model of TNFxcex1 production. Inhibitors of p38 are active in a number of standard animal models of inflammatory diseases, including carrageenan-induced edema in the rat paw, arachadonic acid-induced edema in the rat paw, arachadonic acid-induced peritonitis in the mouse, fetal rat long bone resorption, murine type II collagen-induced arthritis, and Fruend""s adjuvant-induced arthritis in the rat. Thus, inhibitors of p38 will be useful in treating diseases mediated by one or more of the above-mentioned cytokines and/or proteolytic enzymes.
The need for new therapies is especially important in the case of arthritic diseases. The primary disabling effect of osteoarthritis, rheumatoid arthritis and septic arthritis is the progressive loss of articular cartilage and thereby normal joint function. No marketed pharmaceutical agent is able to prevent or slow this cartilage loss, although nonsteroidal antiinflammatory drugs (NSAIDs) have been given to control pain and swelling. The end result of these diseases is total loss of joint function which is only treatable by joint replacement surgery. P38 inhibitors will halt or reverse the progression of cartilage loss and obviate or delay surgical intervention.
Several patents have appeared claiming polyarylimidazoles and/or compounds containing polyarylimidazoles as inhibitors of p38 (for example, Lee et al. WO 95/07922; Adams et al. WO 95/02591; Adams et al. WO 95/13067; Adams et al. WO 95/31451). It has been reported that arylimidazoles complex to the ferric form of cytochrome P450cam (Harris et al. Mol. Eng. 1995, 5, 143, and references therein), causing concern that these compounds may display structure-related toxicity (Howard-Martin et al. Toxicol Pathol. 1987, 15, 369). Therefore, there remains a need for improved p38 inhibitors.
This invention provides compounds, generally described as aryl ureas, including both aryl and heteroaryl analogues, which inhibit p38 mediated events and thus inhibit the production of cytokines (such as TNFxcex1, IL-1 and IL-8) and proteolytic enzymes (such as MMP-1 and MMP-3). The invention also provides a method of treating a cytokine mediated disease state in humans or mammals, wherein the cytokine is one whose production is affected by p38. Examples of such cytokines include, but are not limited to TNFxcex1, IL-1 and IL-8. The invention also provides a method of treating a protease mediated disease state in humans or mammals, wherein the protease is one whose production is affected by p38. Examples of such proteases include, but are not limited to collagenase (MMP-1) and stromelysin (MMP-3).
Accordingly, these compounds are useful therapeutic agents for such acute and chronic inflammatory and/or immunomodulatory diseases as rheumatoid arthritis, osteoarthritis, septic arthritis, rheumatic fever, bone resorption, postmenopausal osteoporosis, sepsis, gram negative sepsis, septic shock, endotoxic shock, toxic shock syndrome, systemic inflammatory response syndrome, inflammatory bowel diseases including Crohn""s disease and ulcerative colitis, Jarisch-Herxheimer reactions, asthma, adult respiratory distress syndrome, acute pulmonary fibrotic diseases, pulmonary sarcoidosis, allergic respiratory diseases, silicosis, coal worker""s pneumoconiosis, alveolar injury, hepatic failure, liver disease during acute inflammation, severe alcoholic hepatitis, malaria including Plasmodium falciparum malaria and cerebral malaria, non-insulin-dependent diabetes mellitus (NIDDM), congestive heart failure, damage following heart disease, atherosclerosis, Alzheimer""s disease, acute encephalitis, brain injury, multiple sclerosis (MS) including demyelation and oligiodendrocyte loss in multiple sclerosis, advanced cancer, lymphoid malignancies, tumor metastasis, pancreatitis, including systemic complications in acute pancreatitis, impaired wound healing in infection, inflammation and cancer, periodontal diseases, corneal ulceration, proteinuria, myelodysplastic syndromes, systemic lupus erythematosus, biliary cirrhosis, bowel necrosis, psoriasis, radiation injury, toxicity following administration of monoclonal antibodies such as OKT3, host-versus-graft reactions including ischemia reperfusion injury and allograft rejections including kidney, liver, heart, and skin allograft rejections, lung allograft rejection including chronic lung allograft rejection (obliterative bronchitis) as well as complications due to total hip replacement, and infectious diseases including tuberculosis, Helicobacter pylori infection during peptic ulcer disease, Chaga""s disease resulting from Trypanosoma cruzi infection, effects of Shiga-like toxin resulting from E. coli infection, effects of enterotoxin A resulting from Staphylococcus infection, meningococcal infection, and infections from Borrelia burgdorferi, Treponema pallidum, cytomegalovirus, influenza virus, Theiler""s encephalomyelitis virus, and the human immunodeficiency virus (HIV).
Accordingly, the present invention is directed to a method for the treatment of diseases mediated by p38, e.g., mediated by one or more cytokines or proteolytic enzymes produced and/or activated by a p38 mediated process, comprising administering a compound of Formula I, 
wherein
A is C6-2-aryl or C5-12-heteroaryl, each optionally substituted, e.g. by C1-4-alkyl, C3-6-cycloalkyl, halogen, xe2x80x94OH, xe2x80x94OR1, xe2x80x94NR12; 
R1 is H or C1-4-alkyl;
R2 and R3 are each independently halogen, xe2x80x94COOR1, xe2x80x94CN, xe2x80x94CONR7R8, or xe2x80x94CH2NHR9;
R5 is C3-5-alkyl;
R6 is C1-6-alkyl;
R7 is hydrogen;
R8 is methyl;
R9 is hydrogen, methyl or xe2x80x94COxe2x80x94R10; and
R10 is hydrogen or methyl optionally substituted by NR62 or COOR6.
In Formula I, suitable heteroaryl groups A include, but are not limited to, 5-10 carbon-atom aromatic rings or ring systems containing 1-2 rings, at least one of which is aromatic, in which one or more, e.g., 1-4 carbon atoms in one or more of the rings can be replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 5-6 atoms. For example, A can be 2- or 3-thienyl, 1,3,4-thiadiazol-2- or -5-yl, 7-indolyl, or 8-quinolinyl, or additionally optionally substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, etc. For example, A can be 4-methylphenyl, 4-fluorophenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl or 5-cyclopropyl-1,3,4-thiadiazol-2-yl.
Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy, etc. throughout include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched isomers such as isopropyl, isobutyl, sec-butyl, tert-butyl, etc.
Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
Suitable aryl groups include, for example, phenyl and 1- and 2-naphthyl.
Suitable halogen groups include F, Cl, Br, and/or I, from one to per-substitution (i.e. all H atoms on a group replaced by a halogen atom) being possible, mixed substitution of halogen atom types also being possible on a given moiety.
Preferred compounds of Formula I include those where R2 or R3 is xe2x80x94COOR1 or xe2x80x94CONR7R8; R1 is C1-4-alkyl; R7 is H; and R8 is methyl, and those where R5 is isopropyl or tert-butyl.
The invention also relates to compounds per se, of Formula II 
wherein
A is C6-12-aryl or C5-12-heteroaryl, each optionally substituted, e.g., by C1-4-alkyl, C3-6-cycloalkyl, halogen, xe2x80x94OH, xe2x80x94OR1, xe2x80x94NR12; 
R1 is H or C1-4-alkyl;
R2 is xe2x80x94COOR1, xe2x80x94CONR7R8, or xe2x80x94CH2NHR9;
R5 is C3-5-alkyl;
R6 is C1-6-alkyl;
R7 is H;
R8 is methyl;
R9 is hydrogen, methyl or xe2x80x94COxe2x80x94R10; and
R10 is hydrogen or methyl optionally substituted by NR62 or COOR6,
with the provisos that A is not unsubstituted naphthyl; and if A is unsubstituted phenyl,
R2 is xe2x80x94COOR1 or xe2x80x94COONR7R8, R1 is C2-4-alkyl, and R5 is isopropyl or tert-butyl.
The invention also relates to compounds of Formula III 
wherein
A is C6-12-aryl or C5-12-heteroaryl, each optionally substituted, e.g., by C1-4-alkyl, C3-6-cycloalkyl, halogen, xe2x80x94OH, xe2x80x94OR1, xe2x80x94NR12; 
R1 is H or C1-4-alkyl;
R3 is xe2x80x94COOR1, xe2x80x94CONR7R8, or xe2x80x94CH2NHR9;
R5 is C3-5-alkyl;
R6 is C1-6-alkyl;
R7 is H;
R8 is methyl;
R9 is hydrogen, methyl or xe2x80x94COxe2x80x94R10; and
R10 is hydrogen or methyl optionally substituted by NR62 or COOR6,
with the provisos that:
(a) A is not unsubstituted naphthyl;
(b) if A is unsubstituted phenyl, then R3 is xe2x80x94COOR1 or xe2x80x94CONR7R8, and R5 is isopropyl or tert-butyl; and
if R5 is isopropyl, then A is not phenyl substituted by halogen, or xe2x80x94OR1.
The invention further relates to compounds of Formula IV 
wherein
A is C6-12-aryl or C5-12-heteroaryl, each optionally substituted, e.g., by C1-4-alkyl, C3-6-cycloalkyl, halogen, xe2x80x94OH, xe2x80x94OR1, xe2x80x94NR12; 
R1 is H or C1-4-alkyl;
R2 is xe2x80x94COOR1, xe2x80x94CONR7R8, or xe2x80x94CH2NHR9;
R5 is C3-5-alkyl;
R6 is C1-6-alkyl;
R7 is H;
R8 is methyl;
R9 is hydrogen, methyl or xe2x80x94COxe2x80x94R10; and
R10 is hydrogen or methyl optionally substituted by NR62 or COOR6,
with the proviso that if A is unsubstituted phenyl, R2 is COOR1 or xe2x80x94CONR7R8, R1 is C2-4-alkyl, and R5 is isopropyl or tert-butyl.
The invention further includes compounds of Formula V 
wherein
A is C6-12-aryl or C5-12-heteroaryl, each optionally substituted, e.g., by C1-4-alkyl, C3-6-cycloalkyl, halogen, xe2x80x94OH, xe2x80x94OR1, xe2x80x94NR12; 
R1 is H or C1-4-alkyl;
R2 is xe2x80x94COOR1, xe2x80x94CONR7R8, or xe2x80x94CH2NHR9;
R5 is C3-5-alkyl;
R6 is C1-6-alkyl;
R7 is H;
R8 is methyl;
R9 is hydrogen, methyl or xe2x80x94COxe2x80x94R10; and
R10 is hydrogen or methyl optionally substituted by NR62 or COOR6.
The present invention is also directed to pharmaceutically acceptable salts of Formula I. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, sulphonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts of Formula I may be formed with a pharmaceutically acceptable cation, for instance, in the case when a substituent group comprises a carboxy moiety. Suitable pharmaceutically suitable cations are well known to those skilled in the art, and include alkaline cations (such as Li+ Na+ or K+), alkaline earth cations (such as Mg+2, Ca+2 or Ba+2), the ammonium cation, and organic cations, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such as those arising from triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, pyridine, N,N-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
The compounds of Formulae I-V are either known in the art or may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general preparative methods are presented to aid one of skill in the art in synthesizing the inhibitors of the invention, with more detailed particular examples being presented in the experimental section.
Methyl 5-alkyl-3-aminothiophene-2-carboxylates may be generated by the reaction of methyl thioglycolate with 2-alkyl-2-chloroacrylonitrile in the presence of a base, preferably NaOMe (Ishizaki et al. JP 6025221; Method A). Urea formation may involve either treatment of the thus formed amine with an isocyanate, or an isocyanate equivalent (Method A), or the conversion of the amine into an isocyanate or an isocyanate equivalent by treatment with phosgene or a phosgene equivalent, followed by reaction with a second amine (Method B). 
If one or more of the aryl groups is substituted with NO2, or its equivalent, this moiety may be reduced either using catalytic hydrogenation, eg. with H2 and palladium-on-carbon, or using a hydride reagent, eg. KBH4 with CuCl, to give the corresponding amine (Method C). 
Transesterification of the urea may undertaken in alcohol solvent using a Lewis acid catalyst, eg. titanium alkoxide, (Method D). 
Alternatively, protection of the amine, eg. as the tert-butyl carbamate, followed by saponification of the ester affords the corresponding amino-protected carboxylic acid (Method E). Ester formation may employ one of a wide variety of standard protocols, eg. carbodiimide-mediated coupling, depending on the amine protecting group. Finally, deprotection, for example using an acid source such as HCl or trifluoroacetic acid for the tert-butyl carbamate, followed by urea formation, as illustrated in either Method A or Method B, will generate ester analogues. 
Amide analogues may be generated in a manner similar to that disclosed in Method E. Protection of the amine, eg. as the benzyl carbamate, followed by amide formation, eg. using an amine in the presence of catalytic cyanide, gives the protected amide (Method F). Deprotection, for example with HBr/acetic acid or catalytic hydrogenation for the benzyl carbamate, followed by urea formation as illustrated in Method A will generate amide analogues. 
Saponfication of 3-aminothiophene-2-carboxylate esters (eg. with KOH) affords the carboxylic acid, which on treatment with phosgene or a phosgene equivalent gives the 2H-thieno[3,2-d]oxazine-2,4(1H)-dione (Method R). Reaction of the thienooxazine with an aryl amine then affords the substituted 2-carboxythienyl urea. Activation, eg. with SOCl2, followed by treatment with an alcohol affords the corresponding ester. Alternately, treatment of the activated intermediate with a primary or secondary amine affords the corresponding amide. 
Amide analogues may also be generated by direct treatment of the methyl ester with an aluminum amide (Method G), followed by urea formation as illustrated in Method A. 
Generation of carboxylic acid analogues may be achieved by hydrolysis of the corresponding esters. For example, catalytic hydrogenation of the C-2 benzyl ester, eg. using H2 and palladium-on-carbon, provides the thiophene-2-carboxylic acid (Method H). 
Ureas containing primary amides may be reduced to the aminomethyl analogues using, for example a BH3.THF solution (Method I). The thus generated amine may then be functionalized as desired. Amide formation may be achieved using acid chlorides or their equivalent, or through standard coupling protocols. For example, the amine may be coupled with an amino-protected glycine, eg. N-BOC-glycine, in the presence of a carbodiimide catalyst, eg. DCC, followed by standard removal of the protecting group, for example using an acid source such as HCl or trifluoroacetic acid for the tert-butyl carbamate (Method I). 
Suitable amines (Axe2x80x94NH2 with A as in Formulae I-V) may be commercially available, or may be generated through any amine forming reaction, such as use of any variation of the Schmidt rearrangement. Thus, for example, a carboxylic acid may be treated with a phosgene equivalent, such as ethyl chloroformate, and an azide source to generate the isocyanate (Method J). The isocyanate may be treated with water to afford the corresponding amine, or directly reacted with a second amine to afford a urea (Method J). 
Lithiation of 2-alkylfurans, using for example n-BuLi, followed by quenching of the 2-furyllithium with CO2 affords the furan-2-carboxylic acid (Method K). Dianion formation, using for example n-BuLi, followed by reaction with tosyl azide, then treatment with a diazomethane equivalent gives the azido ester. Finally, furan analogues of methyl 5-alkyl-3-aminothiophene-2-carboxylates may be generated by reduction of the azide, for example with H2 and palladium-on-carbon (Method K). The aminofuran analogues may be converted into ureas in a similar manner to that illustrated in either Method A or Method B. 
5-Alkyl-3-aminofuran-2-carboxylate esters may also be generated by the reaction of methyl glycolate with 2-alkyl-2-chloroacrylonitrile in the presence of a base (Method L-1). Alternatively, 5-alkyl-3-aminofuran-2-carboxylate esters may be generated from xcex1-cyanoketones (Method L-2). For example, treatment of an xcex1-cyanoketones with an alkyl glycolate under Mitsunobu conditions (eg. triphenylphosphine and a dialkyl azodicarboxylate) affords the xcex2-cyano enol ether. Treatment of the enol ether with a suitable base, such as KOBu-t, NaH, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), then generates the desired aminofuran. Aminofuran analogues may be converted into ureas in a similar manner to that illustrated in either Method A or Method B. 
Amide analogues of aminofurancarboxylic acids may be generated by direct treatment of the methyl ester (from L-1 or L-2) with an aluminum amide (Method M), followed by urea formation as illustrated in Method A. 
Esterification of pyrrole-2-carboxylic acid followed by Friedel-Crafts alkylation affords the 5-alkyl analogue (Method N-1). Electrophilic nitration of the pyrrole with nitric acid in sulfuric acid affords a separable mixture of the 3-nitro compound shown below and the 3,4-dinitro analogue (Method N-1). Reduction of the nitro group, for example using hydrogen and palladium-on-carbon, affords the amine, which may be converted into the urea in a manner similar to that illustrated in Method B (Method N-1), or on treatment with an isocyanate (Method N-2). 
As shown in Method N-3, amide analogues of pyrroles may be generated by conversion of the 5-alkyl-3-nitropyrrole-2-carboxylic acid into the corresponding amide using standard coupling conditions (eg. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, EDCI), followed by reduction of the nitro group and urea formation, as illustrated in Methods N-1 and N-2. 
The 3-nitropyrrole generated in Method N-1 may also be treated with alkylating agents to form the N-alkyl-3-nitropyrrole (Method O). Reduction of the nitro moiety and urea formation proceed in a manner similar to that illustrated in Method N-1. 
Methyl 5-tert-butyl-2-aminothiophene-3-carboxylates may be generated by the reaction of methyl cyanoacetate with 3,3-dimethylbutyraldehyde in the presence of elemental sulfur (Gewald et al. Chem. Ber. 1966, 99, 94; Method P). Urea formation may either involve treatment of the thus formed amine with an isocyanate, or an isocyanate equivalent (Method P), or the convertion of the amine into an isocyanate or an isocyanate equivalent by treatment with phosgene(Method Q) or a phosgene equivalent (Methods S and T), followed by reaction with a second amine. 
Similarly, formation of the 3-carbamoyl-2-thienylamine followed by treatment with an isocyanate affords the corresponding urea (Method U). 
The invention also includes pharmaceutical compositions including a compound of Formulae I-V, and a physiologically acceptable carrier.
The compounds may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations. The term xe2x80x98administration by injectionxe2x80x99 includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired other active ingredients.
Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The compounds may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.
For all regimens of use disclosed herein for compounds of Formulae I-V, the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The daily inhalation dosage regimen will preferably be from 0.01 to 10 mg/Kg of total body weight.
It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be appreciated by one skilled in the art that the specific dose level for a given patient depends on a variety of factors, including specific activity of the compound administered, age, body weight, health, sex, diet, time and route of administration, rate of excretion, etc. It will be further appreciated by one skilled in the art that the optimal course of treatment, ie, the mode of treatment and the daily number of doses of a compound of Formulae I-V or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment tests.
The entire enclosure of all applications, patents and publications cited above and below are hereby incorporated by reference.
The following examples are for illustrative purposes only and are not intended, nor should they be construed to limit the invention in any way.